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Plasma sTNFR1 and IL8 for prognostic enrichment in sepsis trials: a prospective cohort study.

ABSTRACT: BACKGROUND:Enrichment strategies improve therapeutic targeting and trial efficiency, but enrichment factors for sepsis trials are lacking. We determined whether concentrations of soluble tumor necrosis factor receptor-1 (sTNFR1), interleukin-8 (IL8), and angiopoietin-2 (Ang2) could identify sepsis patients at higher mortality risk and serve as prognostic enrichment factors. METHODS:In a multicenter prospective cohort study of 400 critically ill septic patients, we derived and validated thresholds for each marker and expressed prognostic enrichment using risk differences (RD) of 30-day mortality as predictive values. We then used decision curve analysis to simulate the prognostic enrichment of each marker and compare different prognostic enrichment strategies. MEASUREMENTS AND MAIN RESULTS:An admission sTNFR1 concentration?>?8861?pg/ml identified patients with increased mortality in both the derivation (RD 21.6%) and validation (RD 17.8%) populations. Among immunocompetent patients, an IL8 concentration?>?94?pg/ml identified patients with increased mortality in both the derivation (RD 17.7%) and validation (RD 27.0%) populations. An Ang2 level?>?9761?pg/ml identified patients at 21.3% and 12.3% increased risk of mortality in the derivation and validation populations, respectively. Using sTNFR1 or IL8 to select high-risk patients improved clinical trial power and efficiency compared to selecting patients with septic shock. Ang2 did not outperform septic shock as an enrichment factor. CONCLUSIONS:Thresholds for sTNFR1 and IL8 consistently identified sepsis patients with higher mortality risk and may have utility for prognostic enrichment in sepsis trials.

SUBMITTER: Anderson BJ

PROVIDER: S-EPMC6902425 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Plasma sTNFR1 and IL8 for prognostic enrichment in sepsis trials: a prospective cohort study.

Anderson Brian J BJ Calfee Carolyn S CS Liu Kathleen D KD Reilly John P JP Kangelaris Kirsten N KN Shashaty Michael G S MGS Lazaar Aili L AL Bayliffe Andrew I AI Gallop Robert J RJ Miano Todd A TA Dunn Thomas G TG Johansson Erik E Abbott Jason J Jauregui Alejandra A Deiss Thomas T Vessel Kathryn K Belzer Annika A Zhuo Hanjing H Matthay Michael A MA Meyer Nuala J NJ Christie Jason D JD

Critical care (London, England) 20191209 1

<h4>Background</h4>Enrichment strategies improve therapeutic targeting and trial efficiency, but enrichment factors for sepsis trials are lacking. We determined whether concentrations of soluble tumor necrosis factor receptor-1 (sTNFR1), interleukin-8 (IL8), and angiopoietin-2 (Ang2) could identify sepsis patients at higher mortality risk and serve as prognostic enrichment factors.<h4>Methods</h4>In a multicenter prospective cohort study of 400 critically ill septic patients, we derived and vali ...[more]

PMID: 31818332

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Project description:IntroductionVanin-1 plays a pivotal role in oxidative stress and the inflammatory response. However, its relationship with traumatic sepsis remains unknown. The aim of our study was to evaluate whether plasma vanin-1 could be used for the early prediction of traumatic sepsis.MethodsIn this three-stage prospective cohort study, severe trauma patients admitted from January 2015 to October 2018 at two hospitals were enrolled. Plasma vanin-1 levels were measured by enzyme-linked immunosorbent assay (ELISA). The associations among variables and traumatic sepsis were identified by logistic regression models and the receiver operating characteristic (ROC) curve was analyzed to evaluate the diagnostic efficiency.ResultsA total of 426 trauma patients (22 in the discovery cohort, 283 in the internal test cohort, and 121 in the external validation cohort) and 16 healthy volunteers were recruited. The plasma vanin-1 of trauma patients was significantly higher than that of healthy volunteers (P < 0.05). Patients with sepsis had higher plasma vanin-1 than patients without sepsis in the discovery trauma cohort (P < 0.05). In the internal test cohort, plasma vanin-1 at day 1 after trauma was significantly associated with the incidence of sepsis (OR = 3.92, 95% CI 2.68-5.72, P = 1.62 × 10-12). As a predictive biomarker, vanin-1 afforded a better area under the curve (AUC) (0.82, 95% CI 0.77-0.87) than C-reaction protein (CRP) (0.62, 95% CI 0.56-0.68, P < 0.0001), procalcitonin (PCT) (0.66, 95% CI 0.60-0.71, P < 0.0001), and Acute Physiology and Chronic Health Evaluation II (APACHE II) (0.71, 95% CI 0.65-0.76, P = 6.70 × 10-3). The relevance was further validated in the external validation cohort (OR = 4.26, 95% CI 2.22-8.17, P = 1.28 × 10-5), with an AUC of 0.83 (95% CI 0.75-0.89). Vanin-1 could also improve the diagnostic efficiency of APACHE II (AUC = 0.85).ConclusionsOur study demonstrated that plasma vanin-1 increased among trauma patients and was independently associated with the risk of sepsis. Vanin-1 might be a potential biomarker for the early prediction of traumatic sepsis.Trial registrationClinicaltrials.gov Identifier, NCT01713205.

Dataset Information

Plasma sTNFR1 and IL8 for prognostic enrichment in sepsis trials: a prospective cohort study.

Publications

Plasma sTNFR1 and IL8 for prognostic enrichment in sepsis trials: a prospective cohort study.

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